Heat generating biocompatible ceramic materials

ABSTRACT

The present invention pertains to injectable heat generating biocompatible ceramic compositions based on hydraulic calcium aluminate, which can be used for therapeutic treatment in vivo, such as tumour treatment, pain control, vascular treatment, drug activation etc, when curing in situ, and which form a biocompatible solid material that can be left in the body for prolonged periods of time without causing negative health effects. The present invention can also be used to restore the mechanical properties of the skeleton after cancerous diseases.

THE FIELD OF THE INVENTION

[0001] This invention refers to biocompatible ceramic compositions,which before curing show a high degree of formability or mouldability,as well as injectability, and which hardens or cures in-situ undergeneration of elevated temperatures, the levels of which can becontrolled. The compositions according to the present invention , andthe elevated temperatures they generate, can e.g. be used fortherapeutic purposes in vivo, such as tumour treatment, pain control,vascular treatment, etc.

BACKGROUND OF THE INVENTION

[0002] Malignant tumours are traditionally treated by either of threetechniques: surgery, radiation or chemotherapy. Often combinations ofthese techniques are necessary. By surgery, larger tumours of suitablelocations may be removed. Surgery alone is however often not enough, dueto residues of cancerous tissues and twin tumours. Radiation is used forsmaller tumours, particularly in difficult-to-reach locations. By usingradiation techniques, surgery may not be necessary. Chemotherapy suffersfrom other side effects, including necrotic effects on non-cancerouscells.

[0003] A therapeutic procedure explored in some fields of surgery is togenerate heat in vivo at specific locations in the body, and to benefitfrom the heat for therapeutic purposes, such as the treatment of cancercells. Local heat may be achieved by several methods, e.g. withcatheters equipped with elements generating heat by electricalresistivity, which can be controlled to desired locations via thevascular system.

[0004] An alternative technique to achieve heat in-vivo, is to applysmall volumes of slurries or pastes of heat generating materials at thedesired locations, e.g. by injection with needles. The material curesinjected into the body cures through exothermal chemical reactions andthereby generates the desired temperatures. As the temperature rises,local therapeutic effects are generated. Ideally, when the reactions arecompleted, the cured substance should form a biocompatible solidmaterial, which can be left for prolonged periods of time in the bodywithout any negative health effects. Only a few types of therapiesbenefiting from heat generating materials are performed today; the heatgenerating material being PMMA (polymethylmethacrylate) bone cement,despite the lack of biocompatibility.

[0005] Treatment of malignant cancerous tumours, as well as metastasis,myeloms, various cysts, etc, involving the local application of heatgenerating materials in vivo is used to some degree, although it isstill a less frequent treatment technique. The technique involves eitherlocal thermal necrosis or restriction of the nutritional or blood feed,or oxygenation, to the tumours or cells.

[0006] The use of injectable heat generating materials for cancertreatment is particularly suitable for tumours in the skeleton. Theprocedure may involve direct injection of a cell-destroying cement; oralternatively the removal of the tumour by surgery, followed by fillingof the remaining cavity by an in-situ-curing material. The formerprocedure offers at least two advantages: One being that increasedtemperatures during curing reduce the activity of, or kills, residualcancerous tissue. Another effect is that the cement restores themechanical properties of the skeleton, hence reducing the risk offractures due to weakened bone.

[0007] Injectable pastes are also used in combination with radiationtreatment, as when spine vertebrae are first filled with PMMA bonecement injected into the trabecular interior through the pedicles toprovide mechanical stability, followed by radiation treatment of thesame vertebra.

[0008] Similarly, injectable pastes are used for the treatment ofcollapsed osteoporotic vertebrae. The filling of collapsed vertebraewith bone cement reduces the pain and the dimensions of the vertebraemay be restored. Here the heat generation contributes, in addition tothe mechanical stabilization of the vertebrae to the reduction of painin the spine.

[0009] Locally generated heat can be used for the local destruction ofnerves to reduce pain, to destroy the function of blood vessels, and tolocally trigger the effect of drugs.

[0010] As of today, there is no commercialised biocompatible cement,specifically developed for therapeutic purposes by heat generation. Onlystandard bone cement based on polymethyl methacrylate (PMMA) is used.This material may generate sufficient temperatures, but does not showadequate biocompatibility. Due to lack of better alternatives, PMMA bonecement is however well established in surgery.

[0011] Disadvantages With Present Materials

[0012] Today's PMMA based bone cements are developed for orthopaedicneeds, primarily the fixation of hip and knee implants in the skeleton.Despite many disadvantages, these materials are today established inorthopaedics after several decades of use. There is however an on-goingsearch for better, more biocompatible bone cements.

[0013] PMMA based bone cements are not biocompatible materials. Theyhave clear toxic effects caused by leakage of components, such assolvents and non-polymerised monomer. These leakages become particularlyhigh for low viscosity formulations (being injectable) with high amountsof solvents and monomers.

[0014] Ideally in cell therapy with heat generating pastes, the volumeof cured material left after therapy, shall trigger a minimum ofunwanted tissue reactions. This requires a high degree of chemicalstability and biocompatibility.

[0015] For treatment of cancerous bone, the cured material left in theskeleton ideally possesses mechanical properties similar to those ofnatural bone. In particular, an insufficient strength or stiffness isdisadvantageous for load bearing parts of the skeleton. An orthopaediccement shall preferably have an elastic modulus of around 10-20 GPa.Today's PMMA bone cements show elastic modulus around 3 GPa.

[0016] Today's PMMA bone cements cure while generating heat in amountsconsidered excessive for normal orthopaedic use. For use invertebroplasty, some argue that a temperature rise may be advantageous,since it may contribute to reduce pain. However, today's bone cementsoffer no, or very limited, possibilities for the surgeon to control thegenerated temperature.

[0017] Also cements generating low temperatures rises during curing areof interest. A low temperature bone cement based on hydraulic ceramicsis described in the pending Swedish patent application “Ceramic materialand process for manufacturing” (SE-0104441-1), filed 27 Dec. 2001. Insaid patent application the temperature rise due to the hydrationreactions is damped by addition of suitable inert, non-hydraulic phases,which are also favourable for the mechanical properties andbiocompatibility. However, these ceramic materials do not offer themeans to control the heat generation through well controlled phasecompositions of the hydrating ceramic, or controlling the temperature byaccelerators and retarders.

SUMMARY OF THE INVENTION

[0018] In view of the drawbacks associated with the prior art injectablepaste compositions, when used for cell therapy, pain control, vasculartreatments etc, there is a need for an in-situ curing paste-likematerial, which can be injected through fine needles into a position inthe human body, and which cures during a controlled time span undergeneration of a controlled amount of heat, triggering varioustherapeutic effects on targeted tissues and organs, and forming astable, non-toxic and biocompatible solid volume. For use in theskeleton, the cured material should preferably have mechanicalproperties similar to those of bone.

[0019] To fulfil these needs, the present invention uses hydrauliccements, particularly calcium aluminates, which cure exothermically as aresult of chemical reactions with water forming solid ceramic materialsof high biocompatibility and suitable mechanical properties.

[0020] The objective of the present invention is to provide injectableheat generating ceramic biocement compositions, based on hydraulic oxideceramics, primarily calcium aluminates, the curing times and temperatureincrease of which can be controlled to suit clinical needs. Aftercuring, a biocompatible material is formed, which left in the body forprolonged periods of time causes no negative health effects.

[0021] A further object of the present invention is to providecompositions which can function as load bearing bone graft material,restoring the mechanical properties of the skeleton after that tumourshave been removed or treated by radiation, hence reducing the risk offractures due to the weakening of the bone.

[0022] A further object of the present invention is to use thebiocompatible ceramic composition for therapeutic treatment by the heatgenerated from said compositions.

[0023] More particularly, the injectable biocompatible cementcompositions according to the present invention can suitably be used fortherapeutic purposes in vivo, e.g. for cancer treatment, pain relief,vascular treatment, bone restoration and activation of drugs, by theheat they generate when they cure in situ in the body.

[0024] The biocompatible cement compositions according to the presentinvention can further be used to for manufacturing medical implants,orthopaedic implants, dental implant or used as dental filling material,or

[0025] The present invention can also be used for manufacturing of drugcarrier for drug delivery in a patient's body.

[0026] These biocompatible ceramic compositions are in a basic formcomposed of a hydraulic powder raw material, predominantly comprisingcalcium aluminate phases; less than 50 vol. %, preferably less than 10vol. %, of CA₂, based on the total volume of the calcium aluminatephases, more than 50 vol. %, preferably more than 90 vol. % of CA andC₁₂A₇, based on the total volume of the of calcium aluminate phases, andless than 10 vol. %, preferably less than 3 vol. % of C₃A, based on thetotal volume of the of calcium aluminate phases. The compositionaccording to the present invention may optionally contain suitableadditives. The sum of all components amounts to 100%, and the CA-phasesamounts to at least 50%, preferably at least 70%, most preferably atleast 90%.

[0027] The hydraulic powder raw material of the present invention mayfurther comprise the hydraulic powders calcium silicate and/or calciumsulphate in an amount less than 50 vol. % of the total volume ofhydraulic ingredients.

[0028] The compositions according to the present invention may furthercomprise a non-hydraulic filler comprising calcium titanate or any otherternary oxide of perovskite structure according to the formula ABO₃,where O is oxygen and A and B are metals, or any mixture of such ternaryoxides. A in the perovskite structure is selected from the groupcomprising Mg, Ca, Sr or Ba, and that the B in the perovskite structureis selected from the group comprising Ti, Zr, or Hf. The non-hydraulicfiller should be present in an amount of less than 30 vol. %, preferablyless than 10 vol. % of the total volume of the ceramic ingredients.

[0029] In order to increase the bioactivity of the compositionsaccording to the present invention it may further comprise particles orpowder of one or more biocompatible materials selected from the groupcomprising calcium carbonate, calcium phosphate, apatite, fluoroapatite,carbonates-apatites, and hydroxyapatite, the total amount of whichshould be less than 30 vol. % of the total volume of the ceramicingredients.

[0030] The grain size of the powder/particle raw material used ispredominately less than 20 microns, preferably less than 10 microns, andmost preferably less than 3 microns.

[0031] The curing of the compositions according to the present inventioncan be performed in various ways, such as treating the biocompatibleceramic composition with a curing agent, such as a water-based curingliquid or vapour, or by preparing a slurry from said curing liquid andthe biocompatible ceramic composition.

[0032] The curing agent may comprise additives to enhance the generationof heat by controlling the curing time. These additives can be selectedfrom water reducing agents (an agent that reduces the amount of waternecessary to keep a high flowability and to control the viscosity orworkability of the ceramic powder slurry, without having to addexcessive amounts of water), such as polycarboxylic acids, polyacrylicacids, and superplasticisers, such as Conpac 30®. The additivesaccording to the present invention can further be selected fromaccelerator agents, which accelerate the hardening process, and areselected from the group comprising lithium chloride, lithium hydroxide,lithium carbonate, lithium sulphate, lithium nitrate, lithium citrate,calcium hydroxide, potassium hydroxide, potassium carbonate, sodiumhydroxide, sodium carbonate, sodium sulphate and sulphuric acid. In apreferred embodiment of the present invention the accelerator is LiCl,and in a more preferred embodiment of the present invention LiCl ispresent in an amount of 10-500 mg in 100 g of curing liquid. Stillfurther additives according to the present invention are retarderagents, which retard the hardening process, and are selected from thegroup comprising polysaccharide, glycerine, sugars, starch, andcellulose-based thickeners.

[0033] When the compositions according to the present invention areused, in particular, as dental material or implants, the compositionsmay further comprise expansion controlling additives such as fumedsilica and/or calcium silicate. The expansion during curing of thematerial is <0.8%.

[0034] When injected or otherwise introduced into a patient's body, thecompositions according to the present invention can generatetemperatures of 30-150° C. while curing.

[0035] When cured, the compositions according to the present inventionhas a compressive strength of at least 100 MPa.

[0036] The present invention further pertains to a cured biocompatibleceramic composition according the above, and also to a medical devicecomprising said cured biocompatible ceramic composition.

[0037] The present invention further pertains to a method formanufacturing the above-described chemically bonded biocompatibleceramic composition, which method comprises preparing a calciumaluminate/powder mixture of selected phase composition and grain size,and curing said mixture by treating the biocompatible ceramiccomposition with a curing agent, such as a water-based curing liquid orvapour, or by preparing a slurry from said curing liquid and thebiocompatible ceramic composition. The method may also comprise the stepof removing any residual water or organic contamination from the powdermixture before curing.

[0038] The present invention also pertains to a therapeutic methodcomprising the steps of introducing a biocompatible ceramic compositioninto a patient's body and curing said composition, whereby heat isgenerated.

[0039] In a preferred embodiment, the method of generating heat in vivoin a patient's body for therapeutical purposes (e.g. cancer treatment,vascular treatment, pain relief, and activation of drugs), comprises thefollowing steps:

[0040] preparing a calcium aluminate powder mixture comprising less than50 vol. %, preferably less than 10 vol. %, of CA₂, based on the totalvolume of the calcium aluminate phases, more than 50 vol. %, preferablymore than 90 vol. % of CA and C₁₂A₇, based on the total volume of the ofcalcium aluminate phases, less than 10 vol. %, preferably less than 3vol. % of C₃A, based on the total volume of the of calcium aluminatephases, wherein the CA-phases amounts to at least 50%, preferably atleast 70%, most preferably at least 90%, and optionally adding calciumsilicate and/or calcium sulphate in an amount less than 50 vol. % of thetotal volume of hydraulic ingredients,

[0041] The preferred embodiment of the method according to the presentinvention optionally comprises adding non-hydraulic filler in an amountof less than 30 vol. %, preferably less than 10 vol. % of the totalvolume of the ceramic ingredients, optionally adding particles or powderof one or more biocompatible materials, the total amount of which shouldbe less than 30 vol. % of the total volume of the ceramic ingredients,optionally comprises reducing the size of the powder/particle materialto less than 20 microns, preferably less than 10 microns, and mostpreferably less than 3 microns, optionally removing any residual wateror organic contamination from the powder mixture, optionally addingviscosity and workability controlling additives such as water reducingagents, expansion controlling additives, curing accelerator and retarderadditives.

[0042] The preferred embodiment of the method according to the presentinvention also comprises introducing the above-described compositioninto the body at a specific location of therapeutic treatment and curingthe composition in situ in a patient's body.

[0043] The step of curing in the above mentioned method may comprise,prior to the introduction into a patient's body, mixing thebiocompatible ceramic composition with a curing agent, thereby obtaininga slurry, and then introduce the slurry into the desired location insaid patient. The step of curing can also be performed by introducingthe biocompatible ceramic composition into a patient's body and then, insitu at the desired location, treated the composition with a curingagent, such as a water-based solution or water vapour.

BRIEF DESCRIPTION OF THE DRAWINGS

[0044] The present invention will become more fully understood from thedetailed description given below and the accompanying drawings which aregiven by way of illustration only, and thus are not limitative of thepresent invention, and wherein:

[0045]FIG. 1 shows a graph showing the temperature over time generatedby a composition according to the present invention having aconcentration of 0.4 wt. % of LiCl in the hydrating solution.

[0046]FIG. 2 shows a graph showing the temperature over time generatedby a composition according to the present invention having aconcentration of 0.05 wt. % of LiCl in the hydrating solution.

DETAILED DESCRIPTION OF THE INVENTION

[0047] The present invention refers to materials, which cureexothermically under generation of controllable amounts of heat, leadingto elevated temperatures. The heat-generating materials can be used fortherapeutic purposes, involving local heating of cells, cell systems andorgans. The material is applied in the form of slurries, pastes orputties to the desired location e.g. by injection, where it cures into asolid body, generating sufficient temperatures to achieve the desiredeffects, for example for tumour treatment, pain control or vasculartreatments. Materials according to the present invention form analternative to the established PMMA based bone cements.

[0048] The material of the invention cures as a result of hydrationreactions, between ceramic oxide powders and water. Through thehydration a new, strong binding phase composed of hydrates is formed.Ceramic materials curing through hydration are referred to as hydrauliccements. Hydraulic materials include concretes based on Portland cementas well as special ceramics used in dentistry and orthopaedics. Theamount of heat generated during hydration depends on several factors, asis further described below.

[0049] The most relevant hydraulic cement of the present invention iscalcium aluminate. This material consists of phases from the CaO—Al₂O₃system. Several phases are described in the literature, primarily C₃A,C₁₂A₇, CA and CA₂ (C=CaO, A=Al₂O₃), all of which are relevant to thepresent invention. As an alternative embodiment, calcium silicate may beused according to the invention.

[0050] There are several reasons for using calcium aluminates as basesubstance for injectable bio-cements. In comparison to other waterbinding systems, e.g. phosphates, carbonates and sulphates of calcium,the aluminates are characterised by high chemical resistance, highstrength and controlled curing pace. However, silicates have propertiessimilar to those of aluminates and can also be used according to thepresent invention. Also, the curing chemistry based on water makes theprocess relatively unaffected by water-based body fluids. Beforehardening, the material has good workability; it can be used both asslurry or paste. Also, the temperature generation of calcium aluminatesmay be controlled by the details of the phase composition.

[0051] Bio-cement compositions based on calcium aluminate which arerelevant for the present invention are described in the pending Swedishpatent application “Ceramic material and process for manufacturing”(SE-0104441-1), filed 27 Dec. 2001, and in PCT/SE99/01803, “Dimensionstable binding agent systems”, filed 08 Oct. 1999. All additivesdisclosed in these patent applications are relevant to the presentinvention.

[0052] If a powder of calcium aluminate is mixed with water or awater-based solution a process starts, which involves the steps ofdissolution of the calcium aluminates in the water, forming a solutioncontaining ions of calcium and aluminium. At sufficient ionconcentrations, a precipitation of calcium-aluminate hydratescrystallites starts in the liquid. These hydrates build up a new strongbinding phase in the cured solid material.

[0053] The temperatures reached as the hydraulic cement cures depend onseveral factors, the most important ones being: the phase composition ofthe starting calcium aluminate powder, grain size of the startingmaterial powder, the dissolution rate, the hydration rate as controlledby additions of accelerators or retarders, the amount of inert,non-hydraulic phases in the composition, the total volume of hydratingmaterial, and the heat transfer to the environment.

[0054] The hydration of calcium aluminates and calcium silicates is astepwise process. The initially formed hydrates are transformed, inseveral steps, into more stable hydrate phases. At room temperature theinitial hydrate phase is CaO·Al₂O₃·10H₂O, abbreviated as CAH₁₀ (C=CaO,A=Al₂O₃, H=H₂O). The most stable hydrate phase is C₃AH₆. The followingreactions have been identified for hydration of CA:

CA+10H→CAH₁₀  (1)

2CA+11H→C₂AH₈+AH₃  (2)

3CA+12H→C₃AH₆+2AH₃  (3)

2CAH₁₀→C₂AH₈+AH₃+9H  (4)

3C₂AH₈→2C₃AH₆+AH₃+9H  (5)

[0055] All reaction steps are exothermal and heat is developed. Theformation of CAH₁₀ (step 1) produces 245±5 J/g, C₂AH₈ following step 2,280±5 J/g and C₃AH₆ (step 3) 120±5 J/g. The total amount of heatgenerated by standard calcium aluminate cement, consisting mainly of thephases CA and CA₂, is in the range 450 to 500 J/g, as the sum of severalhydration steps. The principles of hydration are similar for calciumsilicate cements.

[0056] The details of the hydration steps are dependent on temperature.The higher the temperature, the more reaction steps may occur within acertain period of time. At room temperature the CAH₁₀ hydrate formsfast, but the conversion to C₃AH₆ arise very slowly, over a period ofmonths. At body temperature (37° C.), C₃AH₆ is formed within a fewhours. At 60° C., the stable hydrate forms within minutes. If severalreaction steps occur fast during the initial hydration, the generatedtemperature is higher. A slower hydration generates lower temperatures.

[0057] There are also other calcium aluminate phases, primarily C₃A,C₁₂A₇ and CA₂, which hydrate as a result of similar reactions. It hasbeen found that the hydration rate depends on the stoichiometry of thestarting phase. The higher the amount of Ca in the starting powder, thefaster the hydration proceeds. Thus, C₃A and C₁₂A₇ cure faster than CAand CA₂. The most probable explanation to this phenomenon is found inthe hydration mechanisms, which first involve dissolution of the calciumaluminate into water, followed by precipitation of hydrates as theconcentrations of Ca- and Al-ions in the solution reach sufficientlevels. For the precipitation of hydrates to be initiated, a higher Ca-than Al-concentration is required.

[0058] Any calcium aluminate cement is a mixture of phases. In general,commercially available cements are composed of CA and CA₂. The phasesC₃A, C₁₂A₇ are not used in commercial cements. Higher amounts of thesefast hydrating calcium aluminate phases however trigger faster hydrationand thereby higher temperatures. Additions of these phases can be usedto steer the temperature generated in a calcium aluminate basedhydraulic ceramic.

[0059] The temperatures generated by the calcium aluminate-basedhydraulic cements according to the present invention can be controlledapproximately to the interval between 30 and 150° C. This entireinterval is of relevance for therapeutic applications. Cell necrosisoccurs from about 45° C., depending also on exposure time. The volumeused for the treatment of osteoporotic spine vertebrae is between 3 and8 ml. For tumour treatment in the spine typically 1-5 ml is needed. Invascular treatment around 0.5-2 ml is typical.

[0060] Controlling the Temperature Rise During Curing

[0061] To generate high temperatures during curing of an injectablebio-cement, at least the following factors need to be taken intoaccount:

[0062] The choice of phase composition in the hydraulic starting powder,and the hydrates that are formed during the initial curing phase.Calcium aluminate phases rich on Ca hydrate faster. For example, anincreased amount of C₃A increases the hydration rate compared to pureCA, and thus higher temperatures. Additions of CA₂ to CA reduce thehydration rate. For heat generating materials, compositions with C₃A andC₁₂A₇ in addition to CA and CA₂ are of particular interest for thepresent invention.

[0063] Of particular interest to the invention are powder compositionswith no or very small amounts of CA₂ (which cure very slowly). Theamount of CA₂ should be lower than 50 vol. %, preferably less than 10vol. %, based on the total of calcium aluminate phases; the majority ofthe calcium aluminates being CA and C₁₂A₇ (with intermediate curingrates), together forming more than 50 vol. %, preferably more than 90vol. %. In addition a smaller part of C₃A is desired, acting asaccelerator or trigger for the curing. The amount of C₃A should be lessthan 10 vol. %, preferably less than 3 vol. % of the total amount ofcalcium aluminate phases. It is unique for the present invention tocontrol the temperature generation of relevant volumes of material bychoosing phase compositions within said intervals.

[0064] The grain size of the starting powder. Smaller grains dissolveand hydrate faster, and thereby generate higher temperatures. The grainsize is controlled by pre-treatment of the hydraulic cement powder withsize reducing methods, e.g. milling. The powder grain size is preferablyless than 10 microns, more preferably less than 3 microns.

[0065] The hydration rate is controlled by the addition of acceleratoragents and/or retarder agents. There are several accelerating additivesknown in the field, e.g. Li-salts such as lithium chloride; as well asretarders, e.g. sugar and various hydrocarbons. With combinations ofaccelerators and retarders special curing effects may be achieved,characterised by a period of no or very slow curing, followed by adelayed stage of fast hydration; a curing cycle of exponentialcharacter.

[0066] In the present invention, accelerators and retarders are notprimarily used to control curing time, as known within the field, butrather to control the temperature generation.

[0067] Of particular interest are compositions cured with LiCl solutionswith about 10-500 mg of LiCl in 100 g of water; as well as compositionscured with solutions containing combinations of accelerators andretarders, e.g. LiCl and sugar, respectively.

[0068] Examples of other salts that may be used as acceleratorsaccording to the present invention are: lithium hydroxide, lithiumcarbonate, lithium sulphate, lithium nitrate, lithium citrate, calciumhydroxide, potassium hydroxide, potassium carbonate, sodium hydroxide,sodium carbonate, sodium sulphate and sulphuric acid.

[0069] Examples of retarders that can be used according to the presentinvention are glycerine, polysaccharide, sugars, starch, andcellulose-based thickeners.

[0070] The ceramic compositions according to the present inventionfurther comprises a component which is a water reducing agent based on acompound selected from the group comprising polycarboxylic acids,polyacrylic acids, and superplasticisers, such as Conpac 30®.

[0071] The amount of inert, non-hydraulic phases in the cementcomposition. Non-hydraulic phases, e.g. non-hydrating oxides, otherceramics or metals, may be added for purposes such as increasedmechanical strength and dimensional stability during hydration. However,for increased temperature generation the amount of non-hydraulic phasesshould be kept low. Non-hydraulic phase concentrations of less than 30vol. % are of relevance to the invention, preferably the amount shouldbe less than 10 vol. % of the total of ceramic ingredients. In addition,non-hydraulic additives may also affect the hydration rate.

[0072] Also, the total volume of hydrating material and the heattransfer to the environment have an influence on the temperature thatcan be obtained. The volume specific heat generation therefore needs tobe higher for smaller volumes of bio-cement, to reach the sametemperature. Or inversely, larger volumes of cement are beneficial togenerate high temperatures.

EXAMPLES Example 1

[0073] This example describes the manufacturing procedure of a ceramiccement consisting of hydrated calcium aluminate without fillers, andserves to illustrate the effect of hydration rate on the generatedtemperatures. Note that the achieved temperatures also depend on otherfactors, such as volume of cured material and heat transportation to theenvironment.

[0074] As raw material, the commercial product Ternal White® fromLafarge Aluminates, is used. This is a calcium aluminate with anAl₂O₃/CaO-ratio of about 70/30.

[0075] The first preparation step was to reduce the grain size of thepowder. This was achieved by ball milling. The milling was performedwith a rotating cylindrical plastic container filled to ⅓ of its volumewith Ternal White powder, and ⅓ with inert silicon nitride millingspheres having a diameter of 10 mm. The milling liquid was iso-propanol,and the total milling time 72 hrs. This milling reduced the size of 90%of the grains to less than 10 μm.

[0076] After milling, the milling spheres were removed by sieving andthe alcohol evaporated. Thereafter the milled powder was burnt at 400°C. for 4 hours, to remove any residual water and organic contamination.

[0077] The second step was to prepare a hydration solution. The solutionconsisted of de-ionised water, to which a water reducing agent and anaccelerator was added. The water reducing agent was selected from agroup of commercial so called superplasticisers, Conpac 30® fromPerstorp AB, known within the field, but any other similar agent wouldalso function. The superplasticiser was added to a concentration of 1wt. % in the water. The accelerator LiCl was added in concentrations of0.05, 0.08, 0.2 or 0.4 wt. %

[0078] The prepared Ternal White powder and the water solutions weremixed so that the ratio of the weight of water to the weight of milledTernal White® powder was 0.35. The powder-liquid mixtures were cured in10 ml plastic containers in air, and the temperature development wasrecorded with a thermocouple introduced into the centre of the cementvolume.

[0079] The results are provided in FIGS. 1 and 2. FIG. 1 shows that aconcentration of 0.4 wt. % of LiCl in the hydrating solution producesabove 90° C. during curing in a room temperature environment, while FIG.2 illustrates the much lower temperatures achieved with a LiClconcentration of 0.05 wt. %, as well as the slower hydration rate.

[0080] This example only serves to illustrate the curing rate effect asachieved by additions of curing accelerators, in this case LiCl, on thetemperature.

Example 2

[0081] This example describes the different curing rates typical forcalcium aluminates of different phases of calcium aluminate.

[0082] Three different calcium aluminate powders composed to 99% of thepure phases CA, C₁₂A₇, CA₃ are used as starting materials.

[0083] Powder grain sizes of less than 10 μm were achieved by milling,as described in Example 1. The milled powders were also burnt at 400° C.for 4 hours, to remove any residuals.

[0084] De-ionised water without any additives was used as hydrationliquid.

[0085] The prepared powders were mixed with water keeping the ratio ofwater to powder constant at 0.35, by weight. The powder-water mixtureswere cured in 10 ml plastic containers in air at room temperature.

[0086] The hydration rates for the CA, C₁₂A₇, CA₃ phases, measured astime to solidification, were measured to 4-6 hours, 5-10 minutes and 2-4seconds, respectively.

1. Biocompatible ceramic composition comprised of calcium aluminatephases of the following composition: less than 50 vol. %, preferablyless than 10 vol. %, of CA₂, based on the total volume of the calciumaluminate phases, more than 50 vol. %, preferably more than 90 vol. % ofCA and C₁₂A₇, based on the total volume of the of calcium aluminatephases, less than 10 vol. %, preferably less than 3 vol. % of C₃A, basedon the total volume of the of calcium aluminate phases, and optionallysuitable additives, wherein the sum of all components amounts to 100%,and wherein the CA-phases amounts to at least 50%, preferably at least70%, most preferably at least 90%.
 2. Biocompatible ceramic compositionaccording to claim 1, characterised in that it further comprises thehydraulic powders calcium silicate and/or calcium sulphate in an amountless than 50 vol. % of the total volume of hydraulic ingredients. 3.Biocompatible ceramic composition according to claim 1, characterised inthat it further comprises a non-hydraulic filler comprising calciumtitanate or any other ternary oxide of perovskite structure according tothe formula ABO₃, where O is oxygen and A and B are metals, or anymixture of such ternary oxides, said filler being present in an amountof less than 30 vol. %, preferably less than 10 vol. % of the totalvolume of the ceramic ingredients.
 4. Biocompatible ceramic compositionaccording to claim 3, characterised in that A in the perovskitestructure is selected from the group comprising Mg, Ca, Sr or Ba, andthat the B in the perovskite structure is selected from the groupcomprising Ti, Zr, or Hf.
 5. Biocompatible ceramic composition accordingto claim 1, characterised in that it further comprises particles orpowder of one or more biocompatible materials selected from the groupcomprising calcium carbonate, calcium phosphate, apatite, fluoroapatite,carbonates-apatites, and hydroxyapatite, the total amount of whichshould be less than 30 vol. % of the total volume of the ceramicingredients.
 6. Biocompatible ceramic composition according to claim 1,characterised in that it further comprises a component which is a waterreducing agent based on a compound selected from the group comprisingpolycarboxylic acids, polyacrylic acids, and superplasticisers, such asConpac 30®.
 7. Biocompatible ceramic composition according to claim 1,characterised in that it further comprises expansion controllingadditives such as fumed silica and/or calcium silicate.
 8. Biocompatibleceramic composition according to claim 1, characterised in that itfurther comprises a water-based curing liquid.
 9. Biocompatible ceramiccomposition according to claim 8, characterised in that the curingliquid further comprises an accelerator agent which accelerates thehardening process, which accelerator agent is selected from the groupcomprising lithium chloride, lithium hydroxide, lithium carbonate,lithium sulphate, lithium nitrate, lithium citrate, calcium hydroxide,potassium hydroxide, potassium carbonate, sodium hydroxide, sodiumcarbonate, sodium sulphate and sulphuric acid.
 10. Biocompatible ceramicmaterial according to claim 9, characterised in that LiCl is present inan amount of 10-500 mg in 100 g of curing liquid.
 11. Biocompatibleceramic composition according to claim 8, characterised in that thecuring liquid further comprises a retarder agent which retards thehardening process, which retarder agent is selected from the groupcomprising polysaccharide, glycerine, sugars, starch, andcellulose-based thickeners.
 12. Biocompatible ceramic compositionaccording to claim 1, characterised in that the grain size of thepowder/particle raw material used is predominately less than 20 microns,preferably less than 10 microns, and most preferably less than 3microns.
 13. Biocompatible ceramic composition according to claim 1,characterised in that the biocompatible ceramic composition generatestemperatures of 30-150° C. when cured in a living human body. 14.Biocompatible ceramic composition according to claim 1, characterised inthat the expansion during curing of the material is <0.8%. 15.Biocompatible ceramic composition according to claim 1, characterised inthat it has a compressive strength of at least 100 MPa. 16.Biocompatible ceramic composition according to claim 1, characterised inthat it is cured.
 17. A medical device comprising a cured biocompatibleceramic composition according to claim
 1. 18. Method for manufacturing abiocompatible ceramic composition according to claim 1, which comprisesthe steps of: preparing a calcium aluminate/powder mixture of selectedphase composition and grain size, and curing said mixture by treatingthe biocompatible ceramic composition with a curing agent, such as awater-based curing liquid or vapour, or by preparing a slurry from saidwater-based curing liquid and the biocompatible ceramic composition. 19.Method of manufacturing according to claim 18, characterised in that itfurther comprises the step of removing any residual water or organiccontamination from the powder mixture before curing.
 20. Medical implantcomprising the biocompatible ceramic composition according to claim 1.21. Orthopaedic implant comprising the biocompatible ceramic compositionaccording to claim
 1. 22. Dental filling material or dental implantcomprising the biocompatible ceramic composition according to claim 1.23. Drug carrier for drug delivery in a patient's body comprising thebiocompatible ceramic composition according to according to claim
 1. 24.Method of using a biocompatible ceramic composition according to claim 1for therapeutic treatment by the heat generated from said compositionswhen curing.
 25. Method of generating heat in vivo in a patient's bodyfor therapeutical purposes (e.g. cancer treatment, vascular treatment,pain relief, and activation of drugs), comprising the following steps:preparing a calcium aluminate powder mixture comprising less than 50vol. %, preferably less than 10 vol. %, of CA₂, based on the totalvolume of the calcium aluminate phases, more than 50 vol. %, preferablymore than 90 vol. % of CA and C₁₂A₇, based on the total volume of the ofcalcium aluminate phases, less than 10 vol. %, preferably less than 3vol. % of C₃A, based on the total volume of the of calcium aluminatephases, and wherein the CA-phases amounts to at least 50%, preferably atleast 70%, most preferably at least 90%. optionally adding calciumsilicate and/or calcium sulphate in an amount less than 50 vol. % of thetotal volume of hydraulic ingredients, optionally adding non-hydraulicfiller in an amount of less than 30 vol. %, preferably less than 10 vol.% of the total volume of the ceramic ingredients, optionally addingparticles or powder of one or more biocompatible materials, the totalamount of which should be less than 30 vol. % of the total volume of theceramic ingredients, optionally reducing the size of the powder/particlematerial to less than 20 microns, preferably less than 10 microns, andmost preferably less than 3 microns. optionally removing any residualwater or organic contamination from the powder mixture, optionallyadding viscosity and workability controlling additives such as waterreducing agents, expansion controlling additives, curing accelerator andretarder additives, and introducing the composition into the body at aspecific location of therapeutic treatment, and curing the compositionin situ in a patient's body.
 26. Method according to claim 25,characterised in that the biocompatible ceramic composition, prior tothe introduction into a patient's body, is mixed with a curing agent,thereby obtaining a slurry.
 27. Method according to claim 25,characterised in that the biocompatible ceramic composition introducedinto a patient's body is treated with a curing agent.
 28. Methodaccording to claim 26, characterised in that the curing agent is awater-based solution or water vapour.
 29. Method according to claim 27,characterised in that the curing agent is a water-based solution orwater vapour.
 30. Therapeutic method comprising the steps of introducinga biocompatible ceramic composition into a patient's body and curingsaid composition, whereby heat is generated.